Diabetes and metabolic syndrome treatment with a novel dual modulator of soluble epoxide hydrolase and peroxisome proliferator-activated receptors

Abstract

N-benzylbenzamides that act as dual soluble soluble epoxide hydrolase (sEH)/peroxisome proliferator-activated receptor γ (PPARγ) modulators and are useful as medications in the treatment of Metabolic Syndrome (MetS) cluster diseases, including diabetes. Methods of making and using the same are further provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Appn. No. 62 / 188,010, filed Jul. 2, 2015, which is incorporated by reference herein for all purposes.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under 1R01DK103616-0A1 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF INVENTION[0003]This invention relates generally to the treatment of Metabolic Syndrome (MetS) and related conditions. More particularly, the present invention is directed to N-benzylbenzamides that act as dual soluble soluble epoxide hydrolase (sEH) / peroxisome proliferator-activated receptor γ (PPARγ) modulators and are useful as medications in the treatment of MetS cluster diseases, including diabetes.BACKGROUND OF THE INVENTION[0004]The metabolic syndrome (MetS) is the name for a group of risk factors such as central obesity, atherogenic dys...

AI Technical Summary

Benefits of technology

[0024]In yet another aspect, the invention provides a method of treating metabolic syndrome in a subject, comprising administering to a subject a therapeutically effective amount of an inventive N-benzylbenzamide compound, wherein soluble epoxide hydrolase (sEH) and peroxisome proliferator-activated receptor gamma (PPARγ) are simultaneously-modulated by the compound thereby treating metabolic syndrome in the subject.

[0025]In preferred embodiments, the therapeutically effective amount provides a half maximal inhibitory concentration (IC50) for sEH and a half maximal effective concentration (EC50) for PPARγ that are less than 1.0 micromolar in the subject.

Problems solved by technology

Nevertheless, already developed individual disorders such as endothelial dysfunction and T2D cannot be completely reversed by this approach and symptoms will worsen with advancing age.

However, this might not be an option in the treatment of MetS patients since insulin resistance and dyslipidemia may worsen during therapy15.

So far, the established therapies to treat or ameliorate T2D are less effective or successful compared to the treatment of other risk factor of the MetS18.

Here, the pharmacokinetic and pharmacologic situation in patients reaches an unfavorable complexity and unpredictable drug-drug interactions can occur.

In addition, medical compliance is at risk.

While therapy costs rise, the probability for medication errors increases3.

However, the clinical use of TZDs is limited due to excessive weight gain, fluid retention and increased osteoporosis risk in treated patients42,43 Meta-analyses of clinical trials have implicated rosiglitazone in increasing the risk of congestive heart failure, myocardial infarction, cardiovascular disease and all-cause mortality leading to tightly restricted access in the United States and a recommendation for market withdrawal in Europe.

Another drawback is the poor effect of TZDs on the occurrence of macrovascular events, although the equilibration of blood glucose levels reduces microvascular complications45.

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